Synthesis of vitamin



Patented June 17; 1947 SYNTHESIS or VITAMIN 1;; V

Stanton A. Harris, Westfield, N. J., assignor to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Original application September 1,

1939, Serial No. 293,131.

Divided and this application January 24, 1942, Serial No. 428,080

8 Claims.

This invention relates to the synthesis of vitamin Ba and to various intermediates employed in the synthesis, and is a division of my co-pending application Serial No. 293,131, filed Sept. 1, 1939.

In a co-pending application, Serial No. 267,603, it is disclosed that 2-methyl-3-amino-4-ethoxymethylaminomethylpyridine dihydrochloride can be diazotized to produce 2-methyl-3-hydroxy-4-ethoxymethyl-5 hydroxymethylpyridine which is converted to vitamin B6 by treatment with concentrated hydrobromic acid to form 2- methyl-3-hydroxy-4,5-di- (bromomethyl) pyridine hydrobromide, boiling the latter compound with water to hydrolyze the bromomethyl radicals to hydroxymethyl radicals, and removing the bromide ion by means of silver or suitable neutralization, concentration and extraction methods.

That application also discloses an alternative method forhydrolyzing 2-methyl-3-hydroxy-4- ethoxymethyl-5-hydroxymethy1pyridine by boiling in a 50% sulfuric acid solution, followed by suitable neutralization, concentration and extraction steps to remove the sulfate radical.

I have discovered that the above methods of obtaining vitamin B6 may be varied, and also, that under certain conditions, some steps can be omitted. This discovery is of importanc in the commercial use of the Synthesis of V tamin 8.

For example, 2 methyl-3 amino 4 alkoxymethyl-5-aminomethylpyridine or its dihydrohalide may be treated with concentrated hydrohalogen acid to form a dihydrohalid of 2-methyl-3-amino-4-halogenmethyl-5 aminomethylpyridine, the latter compound is converted to the dihydrohalide of 2-methyl-3-amino-4 hydroxymethyl-5-aminomethylpyridine, which yields vitamin Ba when diazotized. The treatment of a 2- methyl-3-amino-4-alkoxymethyl-5 aminomethylpyridine dihydrohalide with concentrated hydrohalogen acid may be omitted, and a 2-methyl- 3-amino-4-hydroxymethyl 5 aminomethylpyridine dihydrohalide formed directly by heati g the former compound with a dilute hydroh' logen acid. 3

Alternatively, a dihydrohalide of 2-methyl-3- amino-4-alkoxymethyl 5 aminomethylpyridine may be diazotized to form 2-methyl-3-hydroxy- 4-alkoxymethyl-5-hydroxymethylpyridine which is then treated with a concentrated hydrohalogen acid to form 2 methyl-3-hydroxy-4,5-di- (halogenmethyDpyridine, which is converted to vitamin B6 by hydrolysis. 2-methyl-3-hydroxy- 4-alkoxymethyl-5 hydroxymethylpyridine when heated with dilute hydrochloric acid in water at 150 C. yields vitamin B6 hydrochloride directly.

I have also discovered that, when 2-methyl-3- hydroxy-4 alkoxymethyl fi-hydroxymethylpyridine is treated with 50 or sulfuric acid as disclosed in the above identified co-pending application, during the hydrolysis some ring closure occurs to form 2-methyl-3-hydroxy-4,5-epoxydimethylpyridine of the following structure:

OCH2

HzC 0H CH: N

The hydrochloride of this compound is also formed to some extent when 2-meth'yl-3-hydro1qr-4,5-di-(bromomethyl) pyridine is treated with silver chloride in the presence of water.

The compounds of the present inventon may be represented by th general formulae:

R R1 R OH and CH3 CH3 N wherein R1 is a member selected from the group consisting of amino, aminohydrohalide, and hydroxy, R2 is a member selected from the group consisting of alkoxymethyl, halogenmethyl, and h'ydroxymethyl, R3 is a member selected from the group consisting of aminomethyl, aminomethylhydrohalide, and halogenmethyl, and also hydroxymethyl when R1 is hydroxy and R3 is alkoxymethyl, and wherein R2 and R3 together are epoxydimethyl, R4 is a member selected from the group consisting of alkoxymethyl, halogenmethyl, and hydroxymethyl, R5 is a member selected from the group consisting of halogenmethyl, and also hydroxymethyl when R4 is alkoxymethyl, and wherein R4 and R5 together are epoxydimethyl, and X is a halogen.

The following examples illustrate specific methods of carrying out the present invention, but it is to be understood that chloride.

3 these examples are given by way of illustration and not or limitation.

Example I trate is poured into a test tube, cooled, and crystallization induced by scratching. The product is centrifuged, washed with acetone and ether,

and dried; melting point about 238.5 C. with decomposition. The product is recrystallized by l dissolving in 1 to 2 cc. of water and adding 8 to 10 cc. of alcohol. On standing in ice, crystallization takes place; melting point about 260-265" C., with effervescence if the sample is not preheated. The yield of 2-methyl-3-amino-4-bromoethyl--aminomethylpyridine dihydrobromide is about one gram.

1 gram of 2-methyl-3-amino-4-bromomethyl- 5-aminomethylpyridine dihydrobromide is dissolved in 100 cc. of water and heated on a steam bath for 1 to 2 hours. The mixture is clarified by filtration with charcoal, and the bromine ions are removed by stirring with an excess of silver The filtrate is concentrated almost to dryness under vacuum produced by a water pump, whereupon crystallization takes place. The 2- methyl-3-amino-4 hydroxymethyl 5 aminomethylpyridine dihydrochloride is recrystallized by dissolving in a little water, adding alcohol and scratching; melting point 235-237 C. with decomposition.

Alternatively, one gram of the monohydrate of 2 methyl 3 amino 4 ethoxymethyl 5 aminomethyl-dihydrochloride is dissolved in 15 cc. of 2.5N HCl and heated in a bomb tube at 175-180 C. for four hours. The solution is filtered with a little charcoal, concentrated just to dryness at the water pump and recrystallized from a minimum of 95% alcohol. The yield of the 2- methyl 3 amino 4 hydroxymethyl 5 aminomethylpyridine dihydrochloride is .67 g. or 80% of the theory. M. P. 235-237 C. This compound crystallizes very easily from 95% alcohol or a small amount of water plus alcohol.

1.28 grams of 2-methyl-3-amino-4-hydroxymethyl-S-aminomcthylpyridine dihydrochloride i 22 cc. of distilled water is added simultaneously with a solution of 2.24 grams NaNOz in water to 45 cc, of hot 2.5N HCl.

After completion of the diazotization, the solution is lemon yellow 1 color. This acid solution is concentrated to dryness at the water pump and the residue extract- Example II 300 grams of 2-methyl-3-amino-4-ethoxymeth yl-5-aminomethylpyridine dihydrochloride are 1 dissolved in 430 cc. of water, neutralized with sodium hydroxide in phenol-phthalein and 540 grams sodium nitrite are added. This solution is added slowly to 6500 cc. of hot (90 C.) 2N sulfuric acid with stirring.

There is an immediate evolution of nitrogen, followed by the for- .ing at 195 C.

4 tion is heated for an additional 15 minutes,- treated with Just enough urea to decompose the excess nitrous acid, cooled, and neutralized to pH 7.2 with sodium hydroxide solution, using bromothymol blue asan outside indicator. The slightly reddish solution is concentrated under diminished pressure until sodium sulfate starts to separate. At this point a black, oily layer is formed, which contains most of the desired product. It is dissolved in 2% kg. acetone, filtered from separated sodium sulfate, and evaporated to dryness. The residue is then redissolved in 2% kg. of acetone, filtered from the separated sodium chloride, and evaporated to dryness. It is taken up a third time in 2% kg. ofacetone, filtered from an insoluble material and diluted with an equal volume of ether, whereupon a dark red oil separates. The supernatant liquid is decanted and filtered with the aid of carborafiin. The slightly yellow solution is evaporated to a syrup; yield of 2-methyl-3-hydroxy-4-ethoxymethyl-5- hydroxymethylpyridine 'is 120 grams or about 50% of the theory. Additional material can be obtained from the precipitated oil and by elution of the charcoal with acetone.

Elfty grams of the above material are dissolved in 500 cc. of acetone and treated with dry hydrogen chloride until the solution is acid to wet Congo paper whereupon a brown colored hydrochloride crystallizes out. The addition of ether yield some additional crystals. These crystals are twice recrystallized by dissolving in a. minimum of alcohol and adding an equal volume of acetone and filtering with the aid of carborafiin. The yield is 25.3 g. or 21.5% of the theory based on the original diamine; M P. 135-136 C. Additional crystals may be obtained from the mother liquors.

0.2 gram of 2-methyl-3-hydroxy-4-ethoxymethyl-5hydroxymethylpyridine hydrochloride are dissolved in 6 cc. of concentrated hydrochloric acid and heated for one hour in a constant temperature bath at 132 C. The tube is cooled in ice, opened and crystallization is induced by scratching. The crystals are recrystallized from concentrated hydrochloric acid; melting point about 206 C. after considerable darkening, start- The yield of recrystallized 2- methyl-3-hydroxy-4,5-di (chloromethyl) pyridine hydrochloride is about 0.09 gram or 43%. Additional crystals ,may be obtained from the mother liquor.

0.05 gram of 2-methyl-3-hydroxy-4,5-di- (chloromethyl) pyridine hydrochloride is dissolved in 10 cc. of water and heated for one hour at .100 C. The solution is evaporated almost to dryness and the vitamin B6 hydrochloride recrystallized from alcohol and acetone.

Example III The process described in Example I maybe simplified by dissolving 0.4 gram of 2-methyl-3- hydroxy-i-ethoxymethyl-5 hydroxymethylpyridine hydrochloride in 40 cc. of water containing 2 cc. of 2.5 N hydrochloric acid and heating the solution in a bomb tube ot l55-160 C. for three hours. After cooling, the tube is opened and the contents are evaporated to dryness on a steam bath under reduced pressure. The crystalline residue is recrystallized from 95% alcohol, using charcoal for-clarification; melting point 206-207" 0., mixed melting point with analytically pure vitamin B0 shows no depression. The yield is 2.81 grams mation of a slightly yellow solution. The solu-' or of'theory.

Example 1v In the preparation of vitamin B6 hydrochloride from 2-methyl-3-hydroxy-4,5-di(bromomethyl) pyridine hydrobromide by boiling with water, and removing the bromine ions with silver chloride, a first crop of pure vitamin B6 hydrochloride is obtained. The material from the mother liquor melts at about 195 C. and is recrystallized from 95% alcohol. On the addition of the acetone to the mother liquor, a crystalline material is obtained which melts at 234-235" C. n crystallization from absolute alcohol, the melting point of the 2-methy1-3-hydroxy-4,5- epoxydimethylpyridine hydrochlorid becomes constant at 239-240 C. This compound has some biological activity when fed to vitamin B0 deficient rats.

One gram of 2-methyl-3-hydroxy-4-ethoxymethyl--hydroxymethylpyridine hydrochloride is dissolved in cc. of 60% sulfuric acid and heated until the temperature reaches 145 C. It is then cooled, neutralized to a pH of 7.2 with sodium hydroxide, extracted with acetone which is evaporated to dryness. It is taken up in acetone, filtered, and treated with dry hydrogen chloride. An oil separates which slowly crystallizes. The mother liquor is decanted and treated with ether and additional crystallization takes place slowly. The crystals are recrystallized from absolute alcohol. This compound is identical with the 2 methyl 3-hydroxy-4,5 epoxydimethylpyridine hydrochloride obtained above, as shown by mixed melting point.

Example V 3.7 grams of 2-methyl-3-hydroxy-4,5-epoxydimethylpyridine hydrobromide in 60 cc. of 48% hydrobromic acid is distilled until about one-half of the acid is removed. The solution is cooled in ice, whereupon the 2-methyl-3-hydroxy-4,5- di-(bromomethyl) pyridine hydrobromide crystallizes. The tota1 yield is 6.42 grams (86.5%); M. P. 228.5 C. This compound may be hydrolyzed to vitamin B6, by boiling with water, followed by treatment with silver chloride.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and I am to be limited only by the appended claims.

I claim:

1. A substance selected from the class consisting of 2-methyl-3-hydroxy-4:5-epoxydimethylpyridine and hydrohalide salts thereof.

2. A compound of the formula:

. 6 3. A compound of the formula:

cur-o HO C Bio N HX where HX is a hydrohalic acid.

4- 2-methyl-3-hydroxy-4:5-epoxydimethylpyridine hydrochloride.

5. In the synthesis of vitamin Be, the steps that comprise reacting 2-methyl-3-hydroxy--4-- alkoxymethyl-5-hydroxymethylpyridine hydrohalide with an aqueous sulfuric acid solution, treating the latter mixture with alkali metal hydroxide, extracting with acetone, concentrating to dryness, treating the residue with acetone, removing the alkali metal sulfate, treating the 2 methyl-3-hydroxy-4 5-epoxydimethylpyridine thus formed with a hydrohalic acid and recovering 2-methyl-3-hydroxy-4:5-epoxydimethylpyridine hydrohalide.

6. In the synthesis of vitamin Be the steps that comprise reacting 2-methyl-3-hydroxy-4-ethoxymethyl-5-hydr0xymethylpyridine hydrochloride with an aqueous sulfuric acid solution, treating the latter mixture with sodium hydroxide, extracting with acetone, concentrating to dryness, treating residue with acetone, removing sodium sulfate, treating the 2-methyl-3-hydrox -4z5- epoxydimethylpyridine thus formed with dry hydrogen chloride and recovering 2-methyl-3-hydroxy-4:5-epoxydimethylpyridine hydrochloride.

7. In the synthesis of vitamin Ba, the step that comprises treating 2-methyl-3-hydroxy-4z5-epoxydimethyl-pyridine with a hydrohalic acid to form a 2-methyl-3-hydroxy-4:5-epoxydimethylpyridine hydrohalide.

8. In the synthesis of vitamin Be, the steps that comprise reacting 2-methyl-3-hydroxy-4z5-di- (bromomethyl) pyridine hydrobromide with water and silver chloride to produce vitamin Be hydrochloride and 2-methyl-3-hydroxy-4:E-epoxydimethylpyridine hydrochloride, removing the vitamin Be hydrochloride and recovering 2-methyl-3- hydroxy-4 fi-epoxydimethylpyridine hydrochloride.

STANTON A. HARRIS.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES A. P. C., Zima, Ser. No. 364,568. Published Apr.

Patent No. 2,422,195.

Certificate of Correction STANTON A. HARRIS It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Column 6, lines 2 to 7 inclusive, claim 3, the formula should appear as shown below instead of as in the patent CH3O HO O 1 1O I BX and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Oflice.

Signed-and sealed this 21st day of October, A. D. 1947.

THOMAS F. MURP':

Assistant Oommzssioner of Patents.

June 17, 1947. 

